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A proposed model for BRCA1 repair of erlotinib-induced DNA damage through an H2AX-independent pathway. DNA damage repair involves homologous recombination (HR), usually through the H2AX-dependent pathway. At sites of DNA breakage, the ubiquitin ligase ring-finger protein (RNF)8 is recruited and, together with the second ubiquitin ligase RNF168, it generates ubiquitin chains bound by receptor-associated protein 80 (RAP80), which in turn recruits the final ubiquitin ligase in the cascade, BRCA1. In addition, protein inhibitor of activated STAT (signal transducer and activator of transcription), PIAS1 and PIAS4 SUMO (small ubiquitin-related modifier) ligases, are required for complete accretion of repair proteins to the damaged sites. Depletion of PIAS1 and PIAS4 reduces the response to double-strand breaks by both HR and nonhomologous end-joining (NHEJ), increasing radiosensitivity (RT) (40, 41). Our findings support a predominant predictive role of BRCA1 in patients with EGFR mutations through an H2AX-independent pathway similar to what has been found in experimental studies (27, 29, 39). We speculate that the DNA breakage caused by erlotinib is different from that caused by radiotherapy or platinum-based chemotherapy, and BRCA1 by itself can be a relevant predictive biomarker. In addition, poly(ADP)-ribosylation of proteins by PARP1 is a rapid response to DNA lesions (45). Turning off the DNA damage checkpoint after DNA repair involves the removal of phosphorylated H2AX from the chromatin, followed by its replacement with canonical H2A. This exchange of phosphorylated H2AX for H2A is mediated by facilitates of chromatin transcription (FACT). The ability of FACT to remove phosphorylated H2AX from the chromatin is inhibited by PARP1 (46). Because PARP1 inhibitors downregulate BRCA1 expression (42), further studies could lead to their use in combination with erlotinib in patients with elevated BRCA1 expression.